A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin

Iinuma, Seiichi; Farshi, SS; Ortel, Bernhard; Hasan, Tayyaba

doi:10.1038/bjc.1994.244

Cited by 236 publications

(143 citation statements)

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“…Coproporphyrin and uroporphyrin were excreted into the medium ( Figure 2B) both by human and rat explants exposed to either ALA or its derivatives. The percentage of porphyrins released into the medium was 20% of the total porphyrin synthesized between 2 and 19 h of incubation.The direct fluorescence emission spectra of explants exposed to ALA ( Figure 2C) were characteristic of PpIX with peak emission at 635 and 710 nm as previously demonstrated (Iinuma et al, 1994).The direct fluorescence spectrum of medium ( Figure 2D) showed two prominent peaks at 581 and 616 nm, one of which has been ascribed to hydrophobic porphyrins by Dietel et al (1996), but we have not identified the products.Medium incubated in the presence of ALA without tissue behaved as control explants incubated without ALA, and no porphyrin peaks were found.In both rat and human skin explants incubated with ALA-Me, ALA-He and ALA plus CP94, direct or extracted porphyrins showed similar emission spectra to those illustrated in Figure 2A and C, although with differing fluorescence intensities. Similarly, their corresponding medium profiles were similar to those shown in Figure 2B and D.…”

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confidence: 66%

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

et al. 1999

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Summary Samples of human and rat skin in short-term organ culture exposed to ALA or a range of hydrophobic derivatives were examined for their effect on the accumulation of protoporphyrin IX (PpIX) measured using fluorescence spectroscopy. With the exception of carbobenzoyloxy-D-phenylalanyl-5-ALA-ethyl ester the data presented indicate that, in normal tissues, ALA derivatives generate protoporphyrin IX more slowly than ALA, suggesting that they are less rapidly taken up and/or converted to free ALA. However, the resultant depot effect may lead to the enhanced accumulation of porphyrin over long exposure periods, particularly in the case of ALA-methyl ester or ALA-hexyl ester, depending on the applied concentration and the exposed tissue. Addition of the iron chelator, CP94, greatly increased PpIX accumulation in human skin exposed to ALA, ALA-methyl ester and ALA-hexyl ester. The effect in rat skin was less marked.Keywords: ALA; PDT; ALA derivatives; ALA esters; iron chelators; CP94 1525British Journal of Cancer (1999) 80(10), 1525-1532 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received 9 October 1998 Revised 4 February 1999 Accepted 11 February 1999 Correspondence to: PA Riley Hider et al (1982) and was kindly donated by the Department of Pharmacy. King's College, London and used in a concentration of 100 µg ml -1 (equivalent to 0.6 mM). Synthesis of ALA derivativesNovel ALA derivatives are depicted in Figure 1, and were synthesized as follows.ALA-He was prepared according to the method of Takeya (1992) by reacting ALA with hexanol in the presence of thionyl chloride giving the compound as the hydrochloride (HCl) salt.ALA1-4 were synthesized according to the method of Tanaka et al (1993). The benzyl ester of ALA was prepared by reacting ALA with benzyl alcohol in the presence of thionyl chloride. This was then reacted with the appropriate freshly distilled acid chloride (N-butanoyl, N-pentanoyl, N-hexanoyl or N-heptanoyl chloride) in pyridine. The benzyl ester was removed by hydrogenation using 10% palladium on activated charcoal as a catalyst.ALA5-7 were prepared by reacting a Z-protected amino acid with an ester of ALA using N-cyclohexyl-3,2-morpholinoethyl carbodiimide metho p-toluene sulphonate in DCM as a coupling agent.ALA8 was prepared by reacting N-phthalimidolaevulinic acid with glucosamine tetraacetate using the same coupling agent as for ALA5-7. N-phthalimidolaevulinic acid was prepared using a method adapted from Iida et al (1998). Tetrahydrofurfuryl chloride was reacted with potassium phthalimide for 3 h (cf. the original method in which tetrahydrofurfuryl bromide was reacted for 1 h) giving N-tetrahydrofurfuryl phthalimide. N-phthalimidolaevulinic acid (ALA11) was obtained by oxidation using sodium metaperiodate and ruthenium (III) chloride n-hydrate in aqueous acetonitrile and 1,1,2-trichloro-1,2,2-trifluoroethane, a safer substitute for carbon tetrachloride. Glucosamine tetraacetate was prepared using the four-step procedure of Bergmann and Zervas (1932). The amine of glucos...

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confidence: 66%

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

et al. 1999

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“…This assay has been shown to correlate well with other established measures of cytotoxicity such as colony formation (Iinuma et al, 1994).…”

Section: Cell Survival Assaysmentioning

confidence: 78%

“…5-Aminolaevulinic acid-PDT provides the targeting specificity. 5-Aminolaevulinic acid, an inert pharmacological precursor, remains inactive until it is converted into a photosensitising agent (PpIX) within the target tissue, thereby confining phototoxic chemical events to the target cells and reducing toxic side effects (Kennedy et al, 1990;Iinuma et al, 1994). However, because tumour eradication with ALA-PDT is not always obtained, a new combination that enhances ALA-PDT would be very useful.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

et al. 2006

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Photodynamic therapy (PDT) using 5-aminolaevulinic acid (ALA) to drive production of an intracellular photosensitiser, protoporphyrin IX (PpIX), is a promising cancer treatment. However, ALA-PDT is still suboptimal for thick or refractory tumours. Searching for new approaches, we tested a known inducer of cellular differentiation, methotrexate (MTX), in combination with ALA-PDT in LNCaP cells. Methotrexate alone promoted growth arrest, differentiation, and apoptosis. Methotrexate pretreatment (1 mg l À1 , 72 h) followed by ALA (0.3 mM, 4 h) resulted in a three-fold increase in intracellular PpIX, by biochemical and confocal analyses. After exposure to 512 nm light, killing was significantly enhanced in MTX-preconditioned cells. The reverse order of treatments, ALA-PDT followed by MTX, yielded no enhancement. Methotrexate caused a similar relative increase in PpIX, whether cells were incubated with ALA, methyl-ALA, or hexyl-ALA, arguing against a major effect upon ALA transport. Searching for an effect among porphyrin synthetic enzymes, we found that coproporphyrinogen oxidase (CPO) was increased three-fold by MTX at the mRNA and protein levels. Transfection of LNCaP cells with a CPO-expressing vector stimulated the accumulation of PpIX. Our data suggest that MTX, when used to modulate intracellular production of endogenous PpIX, may provide a new combination PDT approach for certain cancers.

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“…ALA-PDT can be beneficial for acne particularly because it destroys pilosebaceous units as well as P. acnes [52][53][54]. Although its efficacy has been reported with variable mean percentage reduction rates from 32% to 72% according to different authors [55][56][57][58][59][60][61][62], ALA-PDT would not appear to offer significant advantage in the treatment of acne, particularly when the adverse effects of considerable long-lasting post inflammatory hyperpigmentation (PIH) following severe acute local reactions are taken into account, which is especially the case in dark-skinned individuals of Asian origin [19,55,[58][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

Blue and red light combination LED phototherapy for acne vulgaris in patients with skin phototype IV

2006

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Background and Objectives: Blue light is effective for acne treatment, inducing photodynamic destruction of Propionibacterium acnes (P. acnes). This study was designed to investigate the efficacy of combined blue and red light-emitting diode (LED) phototherapy for acne vulgaris. Materials and Methods: Twenty-four patients with mild to moderately severe facial acne were treated with quasimonochromatic LED devices, alternating blue (415 nm) and red (633 nm) light. The treatment was performed twice a week for 4 weeks. Objective assays of the skin condition were carried out before and after treatment at each treatment session. Clinical assessments were conducted before treatment, after the 2nd, 4th, and 6th treatment sessions and at 2, 4, and 8 weeks after the final treatment by grading and lesion counting. Results: The final mean percentage improvements in noninflammatory and inflammatory lesions were 34.28% and 77.93%, respectively. Instrumental measurements indicated that the melanin levels significantly decreased after treatment. Brightened skin tone and improved skin texture were spontaneously reported by 14 patients. Conclusion: Blue and red light combination LED phototherapy is an effective, safe and non-painful treatment for mild to moderately severe acne vulgaris, particularly for papulopustular acne lesions.

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A mechanistic study of cellular photodestruction with 5-aminolaevulinic acid-induced porphyrin

Cited by 236 publications

References 30 publications

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

Comparative effect of ALA derivatives on protoporphyrin IX production in human and rat skin organ cultures

Methotrexate used in combination with aminolaevulinic acid for photodynamic killing of prostate cancer cells

Blue and red light combination LED phototherapy for acne vulgaris in patients with skin phototype IV

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